ERC FUNDED PROJECTS

Exchange of information between different brains usually takes place through the interaction between bodies and the external environment. The ultimate goal of this project is to establish a novel paradigm of brain-to-brain communication based on direct full-optical recording and controlled stimulation of neuronal activity in different subjects. To pursue this challenging objective, we propose to develop optical technologies well beyond the state of the art for simultaneous neuronal “reading” and “writing” across large volumes and with high spatial and temporal resolution, targeted to the transfer of advantageous behaviour in physiological and pathological conditions. We will perform whole-brain high-resolution imaging in zebrafish larvae to disentangle the activity patterns related to different tasks. We will then use these patterns as stimulation templates in other larvae to investigate spatio-temporal subject-invariant signatures of specific behavioural states. This ‘pump and probe’ strategy will allow gaining deep insights into the complex relationship between neuronal activity and subject behaviour. To move towards clinics-oriented studies on brain stimulation therapies, we will complement whole-brain experiments in zebrafish with large area functional imaging and optostimulation in mammals. We will investigate all-optical brain-to-brain information transfer to boost an advantageous behaviour, i.e. motor recovery, in a mouse model of stroke. Mice showing more effective responses to rehabilitation will provide neuronal activity templates to be elicited in other animals, in order to increase rehabilitation efficiency. We strongly believe that the implementation of new technologies for all-optical transfer of behaviour between different subjects will offer unprecedented views of neuronal activity in healthy and injured brain, paving the way to more effective brain stimulation therapies.

2 370 250 €

Start date: 2016-12-01, End date: 2022-05-31

The interest on autophagy, an evolutionarily conserved process in eukaryotes, has enormously increased in the last years, since autophagy is involved in many diseases such as cancer and neurodegenerative disorders. Autophagosome formation is the key process in autophagy. Despite extensive work, the model of autophagosome formation is not yet well established. Some important questions on autophagosome biogenesis remain to be elusive, such as where the bona fide marker protein of autophagosome, LC3, is lipidated, how lipidated LC3 functions in autophagosome formation, and how the proteins for LC3 lipidation and delipidation are involved in autophagosome formation. Although genetic approaches have been useful to identify genes involved in autophagy, they are chronic and thereby the dynamics of phenotypic change cannot be followed, making them not suited for study highly dynamic process such as autophagosome formation. Herein, I propose to develop and use novel chemical probes to address these issues. First, I plan to prepare semi-synthetic caged LC3 proteins and apply them to monitor dynamics of autophagosome formation in the cell in order to address those questions on autophagosome formation. The semi-synthetic LC3 proteins are expected to confer a temporal control and to realize manipulation of protein structure, which renders such studies possible. Second, I intend to develop a versatile approach targeting specific endogenous proteins using a reversible chemically induced dimerization (CID) system, termed as “knock on and off” strategy. I plan to use this approach to elucidate the function of two distinct PI3K complexes in autophagosome formation. On one hand, the establishment of novel approaches will open up a new avenue for studying biological processes. On the other hand, the use of the tool will reveal the mechanism of autophagy.

1 500 000 €

Start date: 2016-09-01, End date: 2021-08-31

During S-phase newly synthesized “sister” DNA molecules become physically connected. This sister chromatid cohesion resists the pulling forces of the mitotic spindle and thereby enables the bi-orientation and subsequent symmetrical segregation of chromosomes. Cohesion is mediated by ring-shaped cohesin complexes, which are thought to entrap sister DNA molecules topologically. In mammalian cells, cohesin is loaded onto DNA at the end of mitosis by the Scc2-Scc4 complex, becomes acetylated during S-phase, and is stably “locked” on DNA during S- and G2-phase by sororin. Sororin stabilizes cohesin on DNA by inhibiting Wapl, which can otherwise release cohesin from DNA again. In addition to mediating cohesion, cohesin also has important roles in organizing higher-order chromatin structures and in gene regulation. Cohesin performs the latter functions in both proliferating and post-mitotic cells and mediates at least some of these together with the sequence-specific DNA-binding protein CTCF, which co-localizes with cohesin at many genomic sites. Although cohesin and CTCF perform essential functions in mammalian cells, it is poorly understood how cohesin is loaded onto DNA by Scc2-Scc4, how cohesin is positioned in the genome, how cohesin is released from DNA again by Wapl, and how Wapl is inhibited by sororin. Likewise, it is not known how cohesin establishes cohesion during DNA replication and how cohesin cooperates with CTCF to organize chromatin structure. Here we propose to address these questions by combining biochemical reconstitution, single-molecule TIRF microscopy, genetic and cell biological approaches. We expect that the results of these studies will advance our understanding of cell division, chromatin structure and gene regulation, and may also provide insight into the etiology of disorders that are caused by cohesin dysfunction, such as Down syndrome and “cohesinopathies” or cancers, in which cohesin mutations have been found to occur frequently.

2 500 000 €

Start date: 2016-10-01, End date: 2021-09-30

The Standard Model of Particle Physics describes the fundamental components of ordinary matter and their interactions. Despite its success in predicting many experimental results, the Standard Model fails to account for a number of interesting phenomena. One phenomenon of particular interest is the large excess of unobservable (Dark) matter in the Universe. This excess cannot be explained by Standard Model particles. A compelling hypothesis is that Dark Matter is comprised of particles that can be produced in the proton-proton collisions from the Large Hadron Collider (LHC) at CERN. Within this project, I will build a team of researchers at Lund University dedicated to searches for signals of the presence of Dark Matter particles. The discovery strategies employed seek the decays of particles that either mediate the interactions between Dark and Standard Model particles or are produced in association with Dark Matter. These new particles manifest in detectors as two, three, or four collimated jets of particles (hadronic jets). The LHC will resume delivery of proton-proton collisions to the ATLAS detector in 2015. Searches for new, rare, low mass particles such as Dark Matter mediators have so far been hindered by constraints on the rates of data that can be stored. These constraints will be overcome through the implementation of a novel real-time data analysis technique and a new search signature, both introduced to ATLAS by this project. The coincidence of this project with the upcoming LHC runs and the software and hardware improvements within the ATLAS detector is a unique opportunity to increase the sensitivity to hadronically decaying new particles by a large margin with respect to any previous searches. The results of these searches will be interpreted within a comprehensive and coherent set of theoretical benchmarks, highlighting the strengths of collider experiments in the global quest for Dark Matter.

1 268 076 €

Start date: 2016-02-01, End date: 2021-01-31